Consistent with former studies and reports, the clinical symptoms of COVID–19 patients in our research were atypical and similar to the common cold or influenza. The onset of symptoms mainly included fever (88.7%), cough (64.2%) and fatigue (34%), and some patients with COVID–19 had lymphopenia[2, 14–16, 18, 19]. In this study, the decrease not only in LYM but also in ALB and A/G were observed, and the CRP level was elevated at the same time.
Moreover, LYM, ALB and A/G were significantly negatively correlated with CT scores of lung involvement, the CRP level was positively correlated with the CT scores of lung involvement at the initial examination and the follow-ups. Recent research also demonstrated that severe patients had more prominent laboratory abnormalities (i.e., lymphopenia, elevated CRP levels) than non-severe patients[15]. The results indicated that the levels of LYM, ALB, A/G, and CRP were significantly correlated with the severity of the COVID–19. These indicators combined with CT features are expected to benefit the early diagnosis and prognosis of COVID–19. Furthermore, LYM, ALB, A/G and CRP could also be used to assess the progression and predict prognosis.
Ground-glass opacity (86.8%) and patchy shadowing (50.9%) under the pleura are most common during the initial CT scan. One of our findings was that the CT images of most patients (especially in Wuhan group) showed an increase in lesion density and size at the short-term follow-up (4 days after admission), suggesting disease progression, although all patients received regular treatments. Changes in laboratory indicators (increased CRP, decreased LYM, ALB, A/G) also suggested progression. Recent studies from Wuhan also found that most patients exhibited progression in the early stage follow-up[12, 18]. The possible explanation is that the coronaviruses interact with and modify the host intracellular environment during infection for rapid replication. Despite careful treatment, time is necessary for COVID–19 patients to build the immune response and produce antibodies to inhibit viral replication. As a result, it is important to control the progression in the early stages of the disease with the utmost effort.
According to the treatment guidelines of COVID–19, RT-PCR assay is the gold standard for the diagnosis of COVID–19 for all patients[7]. Nasopharyngeal swab had been adopted in clinical practice most widely due to its convenience. But recently it was clinically found that some suspected patients’ throat swabs were SARS-CoV–2 negative after repeated RT-PCR tests, while the clinical symptoms and CT manifestation of them were consistent with the performance of COVID–19. At last, the RT-PCR showed SARS-CoV–2 positive after repeated assays or test with deep sputum. The false-negative results in the RT-PCR assay of respiratory secretions may be caused by the low viral load of SARS-CoV–2 in testing samples[20–24]. Both the upper and lower respiratory tract specimens should be analyzed to increase the sensitivity of the test. However, sampling from the lower respiratory tract is not easy to obtain.
Due to the limitations of respiratory tract specimens, too depending on the result of RT-PCR assay will lead to the delay in diagnosis and treatment in a certain extent, and will affect the control of COVID–19 pandemic eventually. It was particularly important to combine epidemiological history, clinical symptoms, laboratory indicators, and CT findings. A detailed history of exposure is critical for the diagnosis. In the correct clinical and laboratory setting, such as fever, cough, progressive lymphopenia and hypoalbuminemia, negative for the other common respiratory pathogens, patients with ground-glass opacities or consolidation on chest CT images, a possible diagnosis of COVID–19 should be considered.
Age, viral load, lung injury score, and albumin, CRP, LDH, LYM (%), LYM, and NEU (%), may be predictors of disease severity[25], and lymphopenia is linked to the increased severity, mortality and dysregulated immunological response[26, 27]. In our study, there was no significant difference in age, gender and duration from onset to admission between Wuhan group and nonWuhan group. However, patients in Wuhan group had a higher tendency of lung involvement CT scores and a lower tendency of LYM, ALB, and A/G at the initial examination and the follow-ups during hospitalization. It was worth noting that, the proportion of severe patients in Wuhan group was 23.3%, and most of them showed progression (66.7%) by increasing involvement range and density of lung opacities on CT imaging at the first follow-up of 4 days, and 69.2% of the patients showed improvement at the second follow-up of 8 days. For patients in nonWuhan group, the proportion of severe patients was 8.7%, and about half of the patients’ CT imaging (47.8%) showed progression at first follow-up, but the improvement account for 100% at the second follow-up.
A single-center study from Zhongnan Hospital of Wuhan University reported a higher proportion of severe patients (26%)[14]. Xu et al reported that compared with COVID–19 patients initially infected in Wuhan, the symptoms of patients in other regions are relatively mild[16]. One possible reason is the limited medical resources. Wuhan is a high-endemic area, and the number of confirmed cases has dramatically increased. The medical resources may be relatively insufficient. The other possible explanation is that the virulence of SARS-CoV–2 may diminish during transmission. Like the severe acute respiratory syndrome coronavirus (SARS-CoV) and the middle east respiratory syndrome coronavirus (MERS-CoV), due to error-prone RNA-dependent RNA polymerase (RdRP) of coronaviruses, SARS-CoV–2 are also prone to mutation and recombination[28, 29]. We speculate that the adaptive evolution of SARS-CoV–2 was occurred in the transmission, resulting in the change of capacity to cause disease. The viral virulence in patients with COVID–19 from Wuhan may be different from that of infected patients who have not been to Wuhan. The viral load in serum or other body liquids might be a useful marker related to disease severity of SARS-CoV–2 infection. Further researches are needed to confirm this speculation.
According to the follow-up laboratory indicators and CT manifestations, though most patients presented progression 4 days after admission, most of them exhibited improvement 8 days after admission, indicating that the disease can be controlled by timely treatment. To date, there are no effective drugs for COVID–19 approved[30, 31]. Treatment is individualized according to the severity of the condition and individual heterogeneity. Treatment measures mainly include symptomatic supportive care, antiviral therapy (lopinavir/ritonavir), oxygen support, respiratory support, antibacterial drugs, and appropriate dose of corticosteroid therapy. It is recommended Traditional Chinese Medicine (TCM) for symptomatic treatment.
Patients can be discharged if they meet the following conditions: body temperature returned to normal at least for 3 days, significant improvement in respiratory symptoms, chest CT performance improved significantly, and respiratory specimens (sputum and nasopharyngeal) nucleic acid tests were negative for consecutive twice (sampling interval at least 1 day). The average length of hospitalization was 13.9 days and the median interval between symptom onset and discharge was 19 days. According to the diagnosis and treatment guidelines[7], self-isolation for 2 weeks after discharge, and follow-up visits to the hospital are recommended 2 and 4 weeks after discharge. The prognosis of patients with COVID–19 at our institution is satisfying. We found that the lung lesions of most patients were partially absorbed within 2 weeks after discharge. Complete absorption of the lesions was observed 2 weeks after discharge in a few nonWuhan patients and after 4 weeks for most patients. Moreover, it may take longer to complete absorption of pneumonia for a couple of severer patients. A study on the prognosis of SARS revealed that pulmonary fibrosis in 62% of patients (15/24) was found at about 5 weeks after discharge[32]. Although the fibrotic change was not found in this study, we have to be cautious about COVID–19, due to the infectivity of some patients with negative results of RT-PCR assay and lung lesions which were not fully absorbed[33]. Therefore, at least 4 weeks are necessary for self-quarantine after discharge as much as possible, which may be helpful in reducing human-to-human infection.
Our study has several limitations. First, the study subjects were limited to discharged patients who had at least twice CT scans during hospitalization and at least 1 CT scan after discharge to ensure more information on clinical and CT features. Thus, the sample size was relatively small and there might be selection biases, further research with larger cohorts is needed to verify our results. Second, our results should be interpreted with caution, because 4 elderly critically ill patients (median age 72.5 years old) still being treated in the respiratory intensive care unit (RICU) and 4 infected children with normal chest CT were not included. Third, the CT score of lung involvement is only related to the range of affected areas, and the changes in the density of the lesion cannot be quantified and need to be improved in future research. Fourth, the viral load and other laboratory indicators, as the potential markers related to the disease severity of COVID–19, should be assessed. Moreover, the role of adaptive evolution in reducing pathogenicity of SARS-CoV–2 also needs to be considered.
In conclusion, CT is an intuitive method with great value in early diagnosis and monitoring of changes in COVID–19. Lymphocytes, C-reactive protein, albumin, and albumin/globulin ratio are sensitive indicators of disease progression and prognosis. Viral pathogenicity may differ between non-endemic areas and core infected areas. Though it is satisfactory that the pneumonia could be completely absorbed in most patients one month after discharge, it is necessary to continue to self-isolation for one month at least after discharge as much as possible.